Abstract SY23-01: Lineage tracing of the intercellular transfer of mitochondria during cancer progression

Abstract The nervous system plays a pivotal role in cancer biology, and pathological investigations have consistently linked intratumoral nerve density to cancer aggressiveness and metastasis. However, the precise impact of cancer-associated neurons on cancer cell biology and the communication channels established at the interface between nerves and cancer remain poorly known. We show that cancer-associated neurons contribute to cancer metabolic plasticity through the transfer of mitochondria from nerves to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed the role of cancer-associated neurons in improving tumor energetics in the breast cancer context. Neurons stimulated by cancer cells in coculture undergo metabolic reprogramming, exhibiting a significant increase in mitochondrial mass coupled with the transfer of their mitochondria into neighboring cancer cells. To precisely track the fate of recipient cancer cells, we developed MitoTRACER, a novel genetic reporter of the cell-cell transfers of mitochondria that permanently mark recipient cells and their progeny. Lineage tracing and fate mapping of cancer cells having acquired mitochondria from neuronal donors in the primary tumor revealed their selective enrichment at metastatic sites following cancer dissemination. Collectively, our data highlight the enhanced capacities of cells that receive mitochondria from neurons in the primary tumor to successfully form distant metastases, shedding light on how the nervous system supports cancer metabolism and metastatic dissemination. Citation Format: Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T. Lin, William Hixson, Terry W. Pierce, Joel F. Andrews, Mikhail F. Alexeyev, Fariba Behbod, Daniel Medina, Jeffrey T. Chang, Gustavo Ayala, Simon Grelet. Lineage tracing of the intercellular transfer of mitochondria during cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY23-01.